This Project will continue its focus on signaling and plasticity as a basis for individual differences in aging outcomes. Against a background of largely preserved structural integrity, alterations in the function of neurons in the medial temporal lobe provide the most reliable indicators of cognitive abilities that depend on this circuitry. The background and preliminary data for this research plan indicate a basis for distinguishing two subpopulations of aged rats that each differ from young. Consistent with recent findings in other components of the overall research program, the CAS region of the hippocampus is particularly noteworthy as an area that undergoes pronounced alterations associated with cognitive impairment. A distinctive profile is also found in this region in aged animals with preserved cognitive function. The Specific Aims of this project will 1) extend the regional analysis of broad molecular profiling in behaviorally characterized aged rats to a paradigm for measuring learning-activated transcription (Aim 2), and 2) assess the efficacy of interventions to gain control over the dysregulaton of cellular function in impaired aged rats and determine whether the such treatments normalize indicators in the molecular profile in both basal and learningactivated conditions along with improved behavioral outcomes (Aim 3). The purpose of studies using interventions based on data in the model is twofold, 1) to allow the test of specific scientific hypotheses, and 2) to examine new avenues into translation approaches for therapy. Test agents under study in the proposed work include 1) antiepileptics (valproate and ABT 769), 2) HDAC inhibitors (sodium butyrate and MS 275), and 3) agonists selective for GABA-A a5 receptors. In Specific Aim 4 we will examine the basis for differential adaptive aging in rats that perform on a par with young adults. That work will explore a new hypothesis concerning alterations in middle-age that may serve an adaptive function in aging outcomes, both neuroprotective and behavioral. Such adaptations would be consistent with a switch in plasticity mechanisms observed in aged unimpaired rats. Finally, research under this project will examine whether signatures of neurocognitive aging in subregions of the hippocampal system in rats have a counterpart in aged monkey brains. Importantly those studies, similar to our research with aged rodents, will use brain tissue obtained from behaviorally characterized young and aged rhesus monkeys. We will ask questions that are based on the conditions of different aging outcomes in the rodent, including 1) overall profiles that relate to cognitive status in the aging primate (e.g. impaired and adaptive), 2) the status of specific genes that are markers of neurocognitive aging in the rodent (CAS and CA1 regions), and 3) pre- and post-synaptic gene expression patterns in arrays of dentate gyrus and entorhinal cortex that may serve as a basis for synaptic failure in the connections formed by the perforant path.